tbuckley/cabot-search huggingface dataset:
Abstract P3093: Gender-specific Functional Dimorphism Of Bone Marrow Endothelial Progenitor Cells: Estrogen Independent Epigenetic Mechanisms
Authors: Charan T Gurrala, Venkata Garikipati, Zhongjian A Cheng, Vandana Mallaredy, Maria Cimini, Darukeshwara Joladarashi, May Truongcao, Chunlin Wang, Anna Maria Lucchese, Grace Huang, Carolina Gonzalez, Ajit Magadum, Rajika Roy, Jayashri Ghosh, Cindy Benedict, Walter J Koch, Raj Kishore
Journal: Circulation Research (2022)

Introduction: Several studies, including our labs, have previously determined the role of estrogen in augmenting EPC-based cardiac repair; however, a direct comparison of therapeutic efficacy of gender-specific stem cells or estrogen-independent mechanisms of gender-specific dimorphism in the reparative properties of BM-EPCs, has not been established. Hypothesis: We hypothesized that epigenetic mechanisms contribute to the sex-specific functional dimorphism of Sca-1+/CD31+ BM-EPCs in regulating cell-homing, pro-angiogenic and anti-inflammatory functions in the ischemic myocardium leading to the enhanced reparative function of female EPCs. Methods: To evaluate our hypothesis, we sorted the male, female and ovariectomized (OVX) mice derived Sca-1+/CD31+ BM-EPCs using MACS multi-sort method. We then subjected the BM-EPCs through a series of cytokine quantifications and epigenetic screening followed by assessment of their therapeutic function in vitro and in vivo . Results: Female and ovariectomized (OVX) female BM-EPCs secrete high levels of pro-angiogenic factors and low levels of pro-inflammatory cytokines compared to male BM-EPCs. Further evaluation of the secretome showed that the male EPCs secreted high levels of interleukins and chemokines compared to female and OVX EPCs. We found that male EPCs exclusively secreted CCL3/Mip-1α. Functional in vitro angiogenic evaluation of the EPC secretome showed higher propensity of female and OVX EPCs than the male EPCs. Post-MI injection of BM-EPCs resulted in remarkable preservation of cardiac structure and functions in both female BM-EPC groups compared to the male EPCs. Male EPC injection resulted in high inflammation in the heart tissue. Epigenetic sequencing of the BM-EPCs for the H3K9me3 mark showed high methylation in male EPCs compared to female and OVX EPCs. The inhibition of histone methyltransferase, Ehmt2/G9a using BIX-01294 upregulated the secretion of inflammatory factors in all EPCs. The conditioned medium from all EPCs with high levels of CCL3 inhibited angiogenesis in vitro . Neutralizing CCL3 in the same medium restored in vitro angiogenesis. Conclusion: Estrogen-independent epigenetic mechanisms govern the enhanced cardiac reparative properties of female BM-EPC.
Abstract P3053: Mitochondrial Calcium Accumulation Drives The Progression Of Non-ischemic Heart Failure: Integrated Lessons From Genetic Mouse Models
Authors: Joanne F Garbincius, Timothy Luongo, Jonathan P Lambert, Adam S Mangold, Devin Kolmetzky, Emma Murray, Alycia Hildebrand, Pooja Jadiya, Rajika Roy, Mary Nwokedi, Jessica Ibetti, Walter J Koch, John W Elrod
Journal: Circulation Research (2022)

Acute mitochondrial calcium ( m Ca 2+ ) uptake stimulates bioenergetics to meet increased ATP demand, but when excessive predisposes to necrotic cell death. A major unresolved controversy is whether chronic alterations in cardiomyocyte m Ca 2+ homeostasis contribute to maladaptive remodeling and contractile dysfunction in non-ischemic heart disease. We hypothesized that cardiomyocyte m Ca 2+ accumulation drives cardiac maladaptation in response to stressors that chronically increase workload and cytosolic Ca 2+ cycling. We subjected mice with adult, cardiomyocyte-specific manipulation of m Ca 2+ uptake through the mitochondrial calcium uniporter ( Mcu deletion, Mcu -cKO; MCU overexpression, MCU-Tg) or m Ca 2+ efflux through the mitochondrial sodium-calcium exchanger, NCLX (NCLX overexpression, NCLX-OE), to chronic pressure or neurohormonal overload. Fractional shortening failed to increase in Mcu -cKO mice over the first days of isoproterenol (Iso) infusion. Mortality was increased in Mcu -cKO mice over this period, and this effect was recapitulated in NCLX-OE mice infused with angiotensin II + phenylephrine (PE), although contractility did not decline in either case. Hypertrophic responses to chronic stress were attenuated in NCLX-OE but not Mcu -cKO hearts, and adenoviral NCLX expression limited mitochondrial metabolism, protein synthesis, and cell growth in neonatal rat cardiomyocytes treated with PE. These data indicate that m Ca 2+ accumulation is required for cardiac hypertrophy, but MCU is not. MCU-Tg hearts decompensated towards failure with 1-2 weeks of Iso. Although these hearts exhibited increased cardiomyocyte necrosis, deletion of the mPTP regulator cyclophilin D failed to rescue contractility, suggesting that m Ca 2+ overload causes cardiac failure, even independent of permeability transition. Fitting with this view, NCLX-OE attenuated the decline in contractile function that occurred with 12-week pressure overload. We conclude that despite initial adaptive effects, sustained m Ca 2+ elevation drives the progression of non-ischemic heart disease triggered by a chronic increase in cardiac workload. Our findings raise concern over proposed therapeutic strategies aiming to augment m Ca 2+ accumulation in heart failure.
Abstract P1010: Acetylation Regulates Yap Subcellular Localization In Heart Regeneration
Authors: Shijie Liu, Vaibhav Deshmukh, Fansen Meng, Jun Wang, James Martin
Journal: Circulation Research (2022)

The core Hippo pathway effector YAP is a transcription co-factor that directs the expression of genes that promote cardiomyocyte renewal. The Hippo kinases phosphorylate YAP and prevent its nuclear localization, underscoring the importance of post-translational modifications on YAP-mediated transcription. Here, we discovered a lysine acetylation-deacetylation cycle-regulated YAP acetylation in cardiomyocytes. acetylated-YAP is prone to cytoplasmic localization and showed reduced YAP activity compared with WT YAP. In addition, mice that harbor the mutation with abolished YAP acetylation showed better heart regeneration than the controls after myocardial infarction. Thus, our study revealed a novel mechanism that acetylation suppresses YAP activity in cardiomyocytes. Given that there are many clinic-approved compounds targeting acetylation enzymes, we believe our study would guide the development of new strategies targeting YAP acetylation for ischemic heart diseases.
Abstract P2112: Human Genetics And Engineered Heart Tissues Link Frail <i>MYH7</i> Alleles To Delayed Maturation And Ventricular Noncompaction
Authors: Tanner O Monroe, Dominic Fullenkamp, Megan Puckelwartz, Elizabeth M McNally
Journal: Circulation Research (2022)

Background: Up to 1% of humans are born with a congenital heart defect. Among those defects is a condition known as left ventricular noncompaction (LVNC), which is defined as the ratio of trabeculated myocardium to compact myocardium exceeding 2.3:1. The process of compaction occurs when the layer of compact cardiomyocytes (CMs) proliferates, while CMs in the trabecular layer quiesce. This differential expansion of the CM layers reduces the trabecular invaginations into the cardiac lumen. Deficient compact CM proliferation or excessive trabecular CM proliferation converge on a similar presentation, collectively referred to as noncompaction. Family and population genetics studies have implicated deleterious variants in sarcomere genes as highly correlated with LVNC (PMID: 18506004, PMID: 3350056); specifically, MYH7 truncations and missense variants that fall within the first 600 amino acids of the beta myosin heavy chain head region. Hypothesis: Reduced contractility in certain MYH7 head domain missense or truncating variants disrupts cardiomyocyte terminal maturation, leading to excessive trabeculation. Results: We identified individuals and families with MYH7 Lys234Asn and Arg243His. Variant carriers had LVNC often in the setting of dilated cardiomyopathy, similar to what has been described with MYH7 truncations. We engineered MYH7 truncations in human induced pluripotent stem cells (hiPSCs) which were differentiated into engineered heart tissues (EHTs) to model the developing heart. In EHTs with MYH7 truncations contractility was reduced by 50%, EHT size increased by 17%, and CM proliferation increased by 40% in EHTs heterozygous for MYH7 truncations (N=6 each). Conclusions and Future Directions: Our observations of impaired differentiation, reduced contractility, and decreased compaction are consistent with LVNC phenotypes. We propose a general model where diminished contractility delays sarcomere maturation, extending the proliferation time of trabecular cardiomyocytes and resulting in excessive trabeculae.
Quality of life measurement in asthma
Authors: PW Jones
Journal: European Respiratory Journal (1995)

<h3>Background:</h3> Higher body mass index (BMI) and obesity is common among youth with bipolar disorder (BD) and is associated with greater psychiatric illness severity, including suicidality. Obesity has been associated with frontal, temporal and subcortical volumetric reductions in adults with BD. We examined the neurostructural correlates of BMI in adolescents early in their course of BD. <h3>Methods:</h3> We processed <i>T</i><sub>1</sub>-weighted images of adolescents with BD and psychiatrically healthy controls using FreeSurfer to derive a priori region of interest (ROI) volumes/cortical thickness for the frontal lobe (FL), prefrontal cortex (PFC) and orbitofrontal cortex (OFC) as well as volumes for the amygdala and hippocampus. General linear models assessed the association between BMI and the ROIs, controlling for age, sex and intracranial volume. We also conducted exploratory within-BD group and whole brain vertex-wise analyses. <h3>Results:</h3> We included 40 adolescents with BD and 48 controls in our analyses. In addition to a main effect of BMI on the ROIs, there were significant diagnosis × BMI interaction effects on FL volumes. In the BD group only, BMI was negatively associated with FL, OFC and PFC cortical thickness. Whole brain analysis of BMI–volume correlations revealed 2 significant interaction clusters: 1 in the medial OFC and 1 in the caudal anterior cingulate cortex, with BD showing a stronger negative correlation. <h3>Limitations:</h3> Reliance on BMI rather than a more nuanced measure of obesity may have influenced the findings. <h3>Conclusion:</h3> Our results suggest that elevated BMI among adolescents with BD is associated with frontal neurostructural differences that are not observed in controls. Prospective studies examining the direction of the observed associations and the effect of BMI optimization on brain structure in adolescents with BD are warranted.
Quantitative importance of asbestos as a cause of lung cancer in a Swedish industrial city: a case-referent study
Authors: B Jarvholm, S Larsson, S Hagberg, S Olling, W Ryd, K Toren
Journal: European Respiratory Journal (1993)

We wanted to assess the quantitative importance of asbestos as a cause of lung cancer. In a case-referent study, the exposure to asbestos, tobacco smoke and some other occupational exposures were compared between 147 cases of lung cancer (100 men, 47 women), 111 hospital referents, and 109 population referents, all below the age of 75 yrs and living in an industrial city. The attributable risk of lung cancer due to asbestos exposure was 16% in men (95% confidence interval 1-31%). No woman had occupational exposure to asbestos. We conclude that in the mid 1980's tobacco smoking was the major attributable risk, being 95% for men and 78% for women, but that in men asbestos was an appreciable contributing factor in the general population of a Swedish industrial city.
Abstract P2001: Vessel Normalization By Targeting Endothelial Cell Plasticity To Improve Cardiac Repair After Myocardial Infarction
Authors: Menggui Huang, Fan Yang, Duo Zhang, Maohuan Lin, Liming Pei, Michael J. Mitchell, Daniel J Rader, Yi Fan, Yanqing A Gong
Journal: Circulation Research (2022)

Ischemic heart disease is a leading cause of death in the world. Formation of new blood vessels is fundamental to cardiac reperfusion and repair after myocardial infarction (MI), and therapeutic promotion of angiogenesis, therefore, has emerged as a promising strategy for treating ischemic heart diseases. However, the therapeutic efficacy is small and transient in most of pro-angiogenic therapy. Here, we characterize unexpectedly prominent vessel aberrancy, albeit a robust angiogenesis, in MI-associated cardiac tissue by 3-dementional light sheet fluorescence imaging. Our single-cell transcriptome analysis of mouse MI tissues with Cdh5-Cre ; Rosa-LSL-tdTomato -mediated endothelial lineage tracing identifies a robust EC plasticity to acquire mesenchymal gene signature in MI-associated ECs, peaked at 1 week and partially retained at 4 and 8 weeks after MI. Moreover, cardiac ECs undergo transcriptional activation to drive mesenchymal phenotypes including over-proliferation, migration and increased permeability, which lead to vessel abnormality after exposure to in vitro ischemic microenvironment. Furthermore, our single-cell and bulk RNA-seq analysis uncovers a PDGF/NF-κB/HIF-1α axis that induces Snail expression and mesenchymal phenotypes in ECs under hypoxia, culminating in aberrant vascularization. Notably, EC-specific knockout of PDGFR-β abrogates mesenchymal gene expression in ECs, attenuates vascular abnormalities in the infarcted tissue, and improves cardiac repair after MI. Interestingly, our single-nuclei analysis uncovers that genetic ablation of PDGFR-β in ECs temporally reprograms cardiomyocyte metabolism and enhances myocyte survival and proliferation. Pharmacological PDGFR inhibition or nanoparticle-based targeted PDGFR-β siRNA delivery normalizes vasculature and improves cardiac function recovery after MI. These findings illustrate a mechanism controlling aberrant neovascularization after ischemia, and suggest that targeting PDGF/Snail-mediated endothelial plasticity may offer exciting opportunities for normalizing vasculature and treating ischemic heart disease.
Abstract P1107: Lem2 Is Essential For Cardiac Development By Maintaining Nuclear Integrity
Authors: Matt Stroud
Journal: Circulation Research (2022)

Background: integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in -encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in heart remains poorly understood. Methods: We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue and cellular analyses. High resolution episcopic microscopy was used for 3D reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided physiological assessment of Lem2 iCKO adult mice. Results: We found that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and L-type calcium channels. Conversely, Lem2 ablation in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age. Conclusions: Our data suggest that Lem2 is critical for integrity at the nascent in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. In contrast, the adult heart is not detectably affected by Lem2 loss, perhaps owing to a more established and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general.
Abstract P1145: Hydrogel Matrix Support Of Suspension-differentiated Hipscs Impacts Resulting <i>In Vitro</i> Cardiac Tissue Functionality
Authors: Mohammadjafar Hashemi, Ferdous Finklea, Hanna Hammons, Yuan Tian, Katherine Wright, Elizabeth A Lipke
Journal: Circulation Research (2022)

Functional in vitro cardiac tissues are needed to provide insight into the cellular level of disease. Previously, we demonstrated hydrogel-encapsulated hiPSCs undergo cardiac differentiation and achieve cardiomyocyte (CM) maturation including T-tubule formation. To investigate the effect of encapsulation on differentiation and cardiac tissue functionality, here we compared PEG-fibrinogen (PF) microsphere (MS)-supported differentiation approach to self-aggregated embryoid body (EB) differentiation. Briefly, hiPSCs were encapsulated or formed into EBs; cardiac differentiation was initiated by Wnt activation and subsequent inhibition. CM content, contractile functionality, drug response, and electrophysiological properties were determined by flow cytometry, microscopy, and optical mapping, respectively.Initial diameter was 673±22 μm (coefficient of variance, COV=0.03) for MS and145±34 μm (COV=0.24) for EBs. The number of CMs produced (differentiation day 10) per initial hiPSC was significantly higher for MS (2.8 ± 1.8) than EBs (0.6±0.12). MS also yielded a higher percentage of CMs; MS-encapsulated hiPSC differentiation resulted in 74.7±13.8% CMs while for EBs it was 56±16.1 % (cTnT+, MF20+, n=14 and 5 batches, respectively, p&lt;0.05). Myocardial contractility was also enhanced in cardiac MS as compared to EBs (similar CM content, day 10); maximum contraction velocity was four times higher for MS than EBs (139±17.5 μm/s versus 33.4±5.1 μm/s) and maximum relaxation velocity was fourteen times higher (97±7.2 μm/s versus 7.4±0.4 μm/s).Furthermore, cardiac MS responded more vigorously to isoproterenol (IP) and propranolol (P) (frequency +124% (IP), - 61% (P), versus +49% (IP) and -27%(P) for EB), suggesting that MS-CM β-adrenergic signaling may be more mature. Calcium transient propagation was more uniform in MS-CMs compared to EB-CMs; calcium transient duration (CTD) at 50% and 80% repolarization and calcium transient velocity were similar. In conclusion, MS supported cardiac differentiation supported higher CM content, faster contractility, and improved drug response in comparison to similarly differentiated EBs, demonstrating the potential of encapsulation to enhance cardiac tissue functionality for disease modeling.
Abstract P3077: The Role Of Neutrophils In Initiating Type I Interferon Response In Myocardial Ischemia/reperfusion
Authors: Maegan L Brockman, Lanfang Wang, John W Calvert, Rebecca D Levit
Journal: Circulation Research (2022)

Background: Inflammation succeeding myocardial ischemia/reperfusion (MI/R) plays a significant role in damaging cardiomyocytes and influencing infarct size, with neutrophils being the most rapid and most numerous cells in the post-MI/R heart. While neutrophils play a role in wound healing, they can cause further damage through the generation of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). We thus hypothesize that double stranded DNA stemming from these NETs activates cGAS-STING signaling in a murine model of MI/R, leading to the production of type I interferons by neutrophils, which worsens reperfusion injury. Methods: Single-cell RNA sequencing was performed on neutrophils isolated from the hearts of mice 24 hours post-MI/R. Additionally, mice underwent MI/R and heart tissues were harvested 6- and 24- hours after reperfusion for ELISA and qPCR analysis. Results: Utilizing single-cell RNA sequencing to better characterize the role of neutrophils and NETs in MI/R, we identified a significant population of neutrophils with a strong type I interferon (IFN) signature recruited to the area of infarct 24 hours post MI/R in a murine model. To further investigate the IFN response seen in this population of neutrophils, we preformed protein and gene expression analysis on heart tissue samples isolated from mice at timepoints in which neutrophils would be present in the area of infarct. Analysis by qPCR shows an increased fold change in gene expression of IFNα (7.22 ± 6.05, n = 3; 3.83 ± 2.22, n = 4) and IFNβ (6.74 ± 5.39, n = 3; 3.64 ± 2.25, n = 4) at 6- and 24- hours post MI/R respectively, compared to sham mice. Furthermore, analysis by ELISA shows a significant increase in IFNβ protein levels in the heart after 6- hours (0.41pg/mg ± 0.04, n =8) compared to sham mice (0.16 pg/mg ± 0.06, n = 7; p ≤ 0.01, Student’s t-test). Conclusions: These data show a rapid increase in type I IFN in the hearts of mice post-MI/R, which implicates neutrophils may be participating in the IFN signaling pathway. Identifying neutrophils as an early source of IFN can provide a potentially new therapeutic target in treating MI/R.
Effects of rhDNase on purulent airway secretions in chronic bronchitis
Authors: E Puchelle, JM Zahm, S de Bentzmann, C Grosskopf, S Shak, D Mougel, JM Polu
Journal: European Respiratory Journal (1996)

Recombinant human deoxyribonuclease (rhDNase) has been demonstrated to reduce in vitro the viscosity and to improve the transport capacity of purulent respiratory mucus in cystic fibrosis. During episodes of exacerbation of chronic bronchitis, the patients generally expectorate purulent mucus. Purulence of mucus is associated with an increased deoxyriboneucleic acid (DNA) concentration. We analyzed in vitro the potential effect of rhDNase on chronic bronchitis mucus transport by the ciliary activity (frog palate model) and by simulated cough (cough machine model), as well as the effect on mucus viscosity (controlled stress rheometer) and surface properties (contact angle). Purulent sputa collected from patients with chronic bronchitis (n = 15) during an episode of exacerbation were incubated for 30 min at 37 degrees C with either rhDNase at two different concentrations (final concentration 2 or 4 micrograms.mL-1) or placebo. The median mucociliary transport rate was significantly improved by rhDNase from 0.68 with placebo to 0.79 and 0.83 with 2 and 4 micrograms.mL-1 of rhDNase, respectively. A significant improvement in mucus cough transport was also induced by rhDNase from 25.5 mm with placebo to 27.0 mm with either 2 or 4 micrograms.mL-1 rhDNase. These improvements in mucus transport capacity were associated with alterations in the physical properties of the mucus. The mucus median control viscosity (511.4 Pa.s) and median contact angle (0.85 rd) significantly decreased to 112.5 Pa.s and 0.74 rd, respectively, in the presence of 4 micrograms.mL-1 of rhDNase. These findings demonstrate that recombinant deoxyribonuclease may exert a beneficial effect on mucus clearance in vitro by altering the viscosity and surface properties of the purulent chronic bronchitic sputum samples.